ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.311G>T (p.Arg104Leu) (rs397516457)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619398 SCV000740033 pathogenic Cardiovascular phenotype 2018-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position
GeneDx RCV000159284 SCV000209230 pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing The R94L pathogenic variant in the TNNT2 gene has been reported in association with hypertrophic cardiomyopathy (Varnava et al., 1999). The R94L variant in the troponin T2 gene has been reported in two affected individuals from a three-generation family with HCM, with marked myocyte disarray and frequent premature sudden death, but minimal myocardial hypertrophy at clinical or macroscopic level, and was not found in 100 normal control individuals (Varnava et al., 1999). Furthermore, the R94L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Palm et al. (2001) showed that pathogenic variants between residues 92-110 of the TNNT2 gene impair tropomyosin binding or TnT enhancement of tropomyosin binding to actin. The authors showed that R94L reduced tropomyosin affinity, in that it eluted about half the ionic strength of the wild type allele (Palm et al., 2001). However, Lu QW et al. (2003) performed an assay using a quartz-crystal microbalance, a sensitive mass-measuring device, and demonstrated that the R94L variant had no effect on the interaction between cTnT and alpha-tropomyosin. The authors also showed that R94L resulted in an increase in the Ca2+ sensitivity of force generation (Lu QW et al., 2003). On the other hand, Harada and Potter (2004) examined the structural and functional properties of R94L variant and showed that it increased the Ca2+ sensitivity of force development but not the maximal force but decreased the change in Ca2+ sensitivity of force development observed in lowering the pH from 7 to 6.5, suggesting this variant can perturb the proper response of cardiac contraction to changes in pH. R94L was also shown to alter the contractile properties of porcine skinned cardiac muscle fibers, in that it decreased the ability to displace the tropomyosin complex in the fibers (Harada and Potter, 2004). R94L represents a non-conservative amino acid substitution that changes the hydrophilicity and electrical charge at a highly conserved site in the troponin T protein, at a position that is conserved across species (Varnava et al., 1999). Missense variants at the same residue (R94C, R94H) and variants in nearby residues (V85L, D86A, F87C, I90M, R92Q, R92L, R92W, E96K, K97N, A104V) have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this region of the protein. In summary, R94L in the TNNT2 gene is interpreted as a pathogenic variant.
Invitae RCV000468546 SCV000541917 pathogenic Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2017-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 94 of the TNNT2 protein (p.Arg94Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (rs397516457, ExAC no frequency). This variant has been reported in a family and multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 10525521, 27532257). ClinVar contains an entry for this variant (Variation ID: 43629). Experimental studies have shown that this missense change affects calcium-dependent force generation (PMID: 14654368, 14722098). A different missense substitution at this codon (p.Arg94Cys) has been determined to be pathogenic (PMID: 10978365). This suggests that the arginine residue is critical for TNNT2 protein function and that other missense substitutions at this position may also be pathogenic. Missense variants that are absent from the ExAC population database have been shown to be significantly overrepresented in individuals with hypertrophic and dilated cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036576 SCV000060231 likely pathogenic Hypertrophic cardiomyopathy 2018-03-19 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000159284 SCV000280519 likely pathogenic not provided 2014-09-03 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. TNNT2 variant Arg94Leu (R94L; c.281G>T at the nucleotide level) The variant has been reported in at least 3 unrelated cases of HCM with moderate segregation data in one family and functional data available. Varnava et al. (1999, 2001) identified this variant in an HCM family with a history of four SCD under age 45. It segregated with the disease in 3 affected family members tested, which included two siblings and their cousin. In addition, a child of one of the siblings who had an abnormal ECG but normal echo at age 6 also had the variant. Melacini et al. (2010) detected the variant in an Italian HCM transplant patient. Pasquale et al. (2011) detected it in an HCM patient followed in the UK. Another change at this same codon, Arg94Cys, has been associated with HCM (we consider that variant to be of uncertain significance, probably disease causing). Variation at nearby loci of TNNT2 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Val85Leu, Asp86Ala, Arg92Trp, Arg92Gln, Arg92Leu, Lys97Asn and Ala104Val (Willott et al. 2010; Harvard Sarcomere Protein Gene Mutation Database). The region between residues ~80-180 of TNNT2 has been described as essential for anchoring the troponin-tropomyosin complex to the thin filament (Hinkle et al. 1999, Palm et al. 2001). In vitro functional data from Palm et al. (2001) suggests that the Arg94Leu variant impairs binding of troponin T to tropomyosin and makes the protein less effective at promoting the binding of tropomyosin to actin. Lu et al. (2003) found it increased the calcium sensitivity of force generation, but had no effect on the protein’s affinity for tropomyosin. Harada & Potter (2004) showed the variant to alter the contractile properties of skinned cardiac fibers, including the response of cardiac contraction to changes in pH. This is a nonconservative amino acid change from a basic, positively-charged Arginine to a nonpolar Leucine. The Arginine at codon 94 is completely conserved across 39 vertebrate species examined. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. Pasquale et al. (2011) report that the SIFT prediction for the variant is “not tolerated”. In total the variant has not been seen in ~6190 published controls and publicly available population datasets. There is no variation at codon 94 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is no variation at this codon listed in dbSNP or 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Varnava et al. (1999) did not find the variant in 100 normal controls. Varnava et al. (2001) did not detect it in at least 90 control individuals. Melacini et al. (2010) did not find it in 400 (Italian?) controls. Pasquale et al. (2011) did not find it in 200 Caucasian controls.

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